2-biphenylyl-2-hydroxy-morpholinium halides



United States Patent 3,117,967 Z-BiPHENYLYL-Z-HYDROXY-MORPHOLINIUMHALIDES Elvin L. Anderson, Moorestown, and Donald E. Rivard,Haddonfield, N.J., assignors to Smith Kline 8: French Laboratories,Philadelphia, Pa., a corporation of Pennsylvania No sawing.

6 Claims.

Filed Apr. 2, 1962, Ser. No. 184,534

This invention relates to novel biphenylyl substituted morpholinederivatives. More specifically, this invention relates toZ-biphenylyl-Z-hydroxymorpholinium halides.

The novel morpholine derivatives of this invention are useful asantiviral agents, particularly against Herpes simplex, hepatitis (MI-1Vand influenza (PR viruses.

The biphenylyl substituted morpholine derivatives are represented by thefollowing fundamental structural formula:

Formula I where:

in which R R R R and X are as defined above for Formula 1. Thus, thehalide and alkanolamine are heated in an unreactive organic solvent,preferably chloroform, and advantageously at the reflux temperature forfrom one to five hours. Cooling separates the crystalline products ingood yields. The reactants employed above are well known to the art.

The following specific examples illustrate the preparation of the novelcompounds of this invention.

Example 1 To a solution of 55 g. of p-phenylphenacyl bromide in 200 ml.of chloroform at reflux is added dropwise with stirring a solution of 18g. of Z-dimethylaminoethanol. The reaction mixture is refluxed for threehours. During the course of the reaction a white precipitate forms. Theprecipitate is collected from the cooled reaction mixture andrecrystallized from ethanol to yield 2-biphenylyl-2- 3,ll?,%7 PatentedJan. 14, 1964 ice hydroxy-4,4-dimethylmorpholinium bromide, M.P. 187-189 C.

Example 2 To a solution of 55 g. of p-phenylphenacyl bromide in 200 ml.of chloroform at reflux-is added dropwise a solution of 23.4 g. ofdiethylaminoethanol in m1. of chloroform. The solution is refluxed untila white precipitate forms (2-3 hours). The white solid is filtered fromthe cooled mixture and recrystallized from an isopropyl alcohol-benzenemixture to give 2-biphenylyl-2-hydroxy-4,4- diethylmorpholinium bromide,M.P. 179181 C.

Example 3 To a solution of g. of p-phenylphenacyl bromide in 200 ml. ofchloroform at reflux is added dropwise with stirring a solution of 24 g.of N-methyldiethanolamine in 50 ml. of chloroform. After one hour ofrefluxing, the product appears as an oil. Cooling, separation of the oiland addition of ether precipitates a solid which is recrystallized froman isopropyl alcohol-benzene mixture to yield2-biphenylyl-2-hydroxy-4(Z-hydroxyethyl) 4 methylmorpholinium bromide,M.P. 169171 C.

Example 4 To a solution of 55 g. of p-phenylphenacyl bromide in 200 ml.of chloroform at reflux is added dropwise with stirring a solution of20.6 g. of 1-dimethylamino-2-pro panel in 50 ml. of chloroform. Themixture is refluxed for two hours and cooled. The product whichprecipitates is collected and recrystallized from a mixture ofbenzeneisopropyl alcohol to yield Z-biphenylyl-Z-hydroxy-4,4,6-trimethylmorpholinium bromide, M.P. 159-162 C.

Example 5 To a solution of 53 g. of a-methyl-p-phenylphenacyl bromide inml. of chloroform at reflux is added drop wise with stirring a solutionof 25 g. of N,N-dimethylaminoethanol in 50 ml. of chloroform. Thesolution is allowed to reflux for several hours until a whiteprecipitate appears. The White solid is collected from the chilledreaction mixture and recrystallized several times from methanol to yield2-biphenylyl-2-hydroxy-3,4,4-trimethylmorpholinium bromide, M.P. 230 C.(decomp).

- Formula I What is claimed is: 1. A chemical compound of the structuralformula:

4 HO OH R1 @Q g 02 N X 50 l 01 6/5CH1 R1 \CIJH s in which:

R is a member selected from the group consisting of methyl and ethyl;

R is a member selected from the group consisting of methyl, ethyl andhydroxyethyl;

'13 R and R are members selected from the group consisting of hydrogenand methyl; and X is a halide anion.

2. A chemical compound of the structural formula:

HO CH2 CH3 l/ \69/ e (I) Br CH2 CH3 3. A chemical compound of thestructural formula:

HO OH: OHzCHa 4. A chemical compound of the structural formula:

HO OH: CHzCHzOH C' m u (I) (IIQCH:

HO OH: CH 5 @Q \t/ (I) CIEOHS 6. A chemical compound of the structuralformula:

CH; 15 HO (3H CH3 \g/ (I) ()EQHQ ofiz No references cited.

1. A CHEMICAL COMPOUND OF THE STRUCTURAL FORMULA: